The American Cancer Society estimates that approximately 224,390 new cases of lung cancer, of which 85% to 90% will be non-small cell lung cancer (NSCLC), will be diagnosed in the United States in 2016. About 158,080 patients will die from the disease, leading to more deaths from lung cancer than colon, breast, and prostate cancer combined.1
As with many other cancer types, kinase inhibitors have drastically improved the treatment landscape for metastatic NSCLC. Although the mainstay of advanced or metastatic NSCLC systemic therapy continues to be chemotherapy, the U.S. Food and Drug Administration (FDA) has now approved erlotinib, afatinib, gefitinib, and osimertinib for patients with sensitizing epidermal growth factor receptor (EGFR) mutation-positive tumors.
Likewise, crizotinib, ceritinib, alectinib are indicated for patients with anaplastic lymphoma kinase (ALK) rearrangements. Immunotherapeutic agents like bevacizumab, pembrolizumab, ramucirumab, and nivolumab are also used in this setting.
The NSCLC treatment pipeline includes additional targeted therapies, immunotherapies, and chemotherapies that have already demonstrated safety and efficacy in phase 2 and 3 trials. Cancer Therapy Advisor spoke with Gregory A. Masters, MD, attending physician at the Helen F. Graham Cancer Center in Newark, Delaware, to clarify which therapies he believes are the most promising for metastatic NSCLC treatment.
“There has been a really tremendous shift in the treatment for NSCLC,” said Dr Masters, who is also an associate professor at the Thomas Jefferson University Medical School in Philadelphia, Pennsylvania, and has served on the Thoracic Malignancies Steering Committee at the National Cancer Institute.
“Ten or 15 years ago, we were using chemotherapy almost exclusively,” Dr Masters explained. “We were just starting to use some of the targeted drug but without a lot of understanding of how and why they worked or for whom they worked best. We were at a bit of a standstill until the molecular biology started to catch up.
“It is really over the last 5 or 6 years that we have understood all of these molecular mutations that occur in NSCLC, and how many of those can be driving forces for the growth and spread of cancer,” Dr Masters told Cancer Therapy Advisor. “Developing drugs that target those mechanisms of growth has really changed the way we treat patients.”
Rociletinib is an oral kinase of mutant EGFR, including the T790M mutation that is often present in tumors that are resistant to other kinase inhibitors. In a single-arm, phase 1/2 study of 345 patients with EGFR-mutant NSCLC, who had received at least 1 EGFR inhibitor previously, researchers found that the overall response rate with rociletinib was 49% among those harboring a T790M mutation and 36% among others. The most frequently reported adverse events were hyperglycemia (40%), diarrhea (28%), nausea (23%), fatigue (21%), and decreased appetite (17%).2
In April 2016, however, the FDA voted 12 to 1 in favor of requiring Clovis Oncology to complete a phase 3 trial to evaluate the efficacy and safety of rociletinib in this treatment setting. Their decision was based on the lack of comparative data with another standard therapy, as well as uncertainty as to why patients were switched from the recommended 500 mg dose to the 625 mg dose.
“Both rociletinib and osimertinib were developed for patients who developed a T790M mutations to an EGFR inhibitor. Osimertinib was approved by the FDA, possibly in part because it was first, but I believe the studies showed a little better toxicity profile,” Dr Masters said. “There were concerns about toxicity that the FDA thought that rociletinib did not match up to osimertinib.”
The phase 3 trial evaluating the efficacy and safety of rociletinib will be completed in 2018.